Glucagon-like peptide-1 analogs activate AMP kinase leading to reversal of the Warburg metabolic switch in breast cancer cells.

Breast cancer (BC) is associated with type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide (GLP)-1 regulates post-prandial insulin secretion, satiety, and gastric emptying. Several GLP-1 analogs have been FDA-approved for the treatment of T2DM and obesity. Moreover, GLP-1 regulates various metabolic activities across different tissues by activating metabolic signaling pathways like adenosine monophosphate (AMP) activated protein kinase (AMPK), and AKT. Rewiring metabolic pathways is a recognized hallmark of cancer, regulated by several cancer-related pathways, including AKT and AMPK. As GLP-1 regulates AKT and AMPK, we hypothesized that it alters BC cells' metabolism, thus inhibiting proliferation. The effect of the GLP-1 analogs exendin-4 (Ex4) and liraglutide on viability, AMPK signaling and metabolism of BC cell lines were assessed. Viability of BC cells was evaluated using colony formation and MTT/XTT assays. Activation of AMPK and related signaling effects were evaluated using western blot. Metabolism effects were measured for glucose, lactate and ATP. Exendin-4 and liraglutide activated AMPK in a cAMP-dependent manner. Blocking Ex4-induced activation of AMPK by inhibition of AMPK restored cell viability. Interestingly, Ex4 and liraglutide reduced the levels of glycolytic metabolites and decreased ATP production, suggesting that GLP-1 analogs impair glycolysis. Notably, inhibiting AMPK reversed the decline in ATP levels, highlighting the role of AMPK in this process. These results establish a novel signaling pathway for GLP-1 in BC cells through cAMP and AMPK modulation affecting proliferation and metabolism. This study suggests that GLP-1 analogs should be considered for diabetic patients with BC.

The determinants of metabolic discrepancies in aerobic glycolysis: Providing potential targets for breast cancer treatment.

Altered aerobic glycolysis is the robust mechanism to support cancer cell survival and proliferation beyond the maintenance of cellular energy metabolism. Several investigators portrayed the important role of deregulated glycolysis in different cancers, including breast cancer. Breast cancer is the most ubiquitous form of cancer and the primary cause of cancer death in women worldwide. Breast cancer with increased glycolytic flux is hampered to eradicate with current therapies and can result in tumor recurrence. In spite of the low order efficiency of ATP production, cancer cells are highly addicted to glycolysis. The glycolytic dependency of cancer cells provides potential therapeutic strategies to preferentially kill cancer cells by inhibiting glycolysis using antiglycolytic agents. The present review emphasizes the most recent research on the implication of glycolytic enzymes, including glucose transporters (GLUTs), hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase-A (LDHA), associated signalling pathways and transcription factors, as well as the antiglycolytic agents that target key glycolytic enzymes in breast cancer. The potential activity of glycolytic inhibitors impinges cancer prevalence and cellular resistance to conventional drugs even under worse physiological conditions such as hypoxia. As a single agent or in combination with other chemotherapeutic drugs, it provides the feasibility of new therapeutic modalities against a wide spectrum of human cancers.

Shikonin-Loaded Hollow Fe-MOF Nanoparticles for Enhanced Microwave Thermal Therapy.

Microwave (MW) thermal therapy has been widely used for the treatment of cancer in clinics, but it still shows limited efficacy and a high recurrence rate owing to non-selective heat delivery and thermo-resistance. Regulating glycolysis shows great promise to improve MW thermal therapy since glycolysis plays an important role in thermo-resistance, progression, metabolism, and recurrence. Herein, we developed a delivery nanosystem of shikonin (SK)-loaded and hyaluronic acid (HA)-modified hollow Fe-MOF (HFM), HFM@SK@HA, as an efficient glycolysis-meditated agent to improve the efficacy of MW thermal therapy. The HFM@SK@HA nanosystem shows a high SK loading capacity of 31.7 wt %. The loaded SK can be effectively released from the HFM@SK@HA under the stimulation of an acidic tumor microenvironment and MW irradiation, overcoming the intrinsically low solubility and severe toxicity of SK. We also find that the HFM@SK@HA can not only greatly improve the heating effect of MW in the tumor site but also mediate MW-enhancing dynamic therapy efficiency by catalyzing the endogenous H2O2 to generate reactive oxygen species (ROS). As such, the MW irradiation treatment in the presence of HFM@SK@HA in vitro enables a highly improved anti-tumor efficacy due to the combined effect of released SK and generated ROS on inhibiting glycolysis in cancer cells. Our in vivo experiments show that the tumor inhibition rate is up to 94.75% ± 3.63% with no obvious recurrence during the 2 weeks after treatment. This work provides a new strategy for improving the efficacy of MW thermal therapy.

Glycolysis-based drug delivery nanosystems for therapeutic use in tumors and applications.

Tumor cells are able to use glycolysis to produce energy under hypoxic conditions, and even under aerobic conditions, they rely mainly on glycolysis for energy production, the Warburg effect. Conventional tumor therapeutic drugs are unidirectional, lacking in targeting and have limited therapeutic effect. The development of a large number of nanocarriers and targeted glycolysis for the treatment of tumors has been extensively investigated in order to improve the therapeutic efficacy. This paper reviews the research progress of nanocarriers based on targeting key glycolytic enzymes and related transporters, and combines nanocarrier systems with other therapeutic approaches to provide a new strategy for targeted glycolytic treatment of tumors, providing a theoretical reference for achieving efficient targeted treatment of tumors.

Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma.

The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the NAD+/NADH and pyruvate/lactate ratios and also the α-ketoglutarate/2-hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and ß-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and ß-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma. SIGNIFICANCE: Targeting cancer metabolism using the mitochondrial uncoupler niclosamide ethanolamine leads to methylome reprogramming and differentiation in neuroblastoma, providing a therapeutic opportunity to reverse the Warburg effect and suppress tumor growth. See related commentary by Byrne and Bell, p.167.

LncCCAT1 interaction protein PKM2 upregulates SREBP2 phosphorylation to promote osteosarcoma tumorigenesis by enhancing the Warburg effect and lipogenesis.

Pyruvate kinase M2 (PKM2) plays an important role in the consumption of glucose and the production of lactic acid, the striking feature of cancer metabolism. The association of PKM2 with osteosarcoma (OS) has been reported but its role in OS has yet to be elucidated. To study this, PKM2­bound RNAs in HeLa cells, a type of cancer cells widely used in the study of molecular function and mechanism, were obtained. Peak calling analysis revealed that PKM2 binds to long noncoding RNAs (lncRNAs), which are associated with cancer pathogenesis and development. Validation of the PKM2­lncRNA interaction in the human OS cell line revealed that lncRNA colon cancer associated transcript­1 (lncCCAT1) interacted with PKM2, which upregulated the phosphorylation of sterol regulatory element­binding protein 2 (SREBP2). These factors promoted the Warburg effect, lipogenesis, and OS cell growth. PKM2 appears to be a key regulator in OS by binding to lncCCAT1. This further extends the biological functions of PKM2 in tumorigenesis and makes it a novel potential therapeutic for OS.

Methylglyoxal produced by tumor cells through formaldehyde-enhanced Warburg effect potentiated polarization of tumor-associated macrophages.

Environmental exposure to formaldehyde is known to be associated with cancers and many other diseases. Although formaldehyde has been classified as a group I carcinogen, the molecular mechanisms of its carcinogenicity are still not fully understood. Formaldehyde is also involved in the folate-driven one­carbon metabolism, and excess amount of formaldehyde was found to interfere with other metabolic pathways including glycolysis, which can enhance Warburg effect and induce immunosuppression in tumor microenvironment. Therefore, different tumor cells and THP-1 derived macrophages were utilized to explore the metabolism-related effects induced by formaldehyde at environmentally relevant concentrations. Significant increases of glucose uptake, glycolysis levels, HIF-1α signaling and methylglyoxal production were observed in tumor cells treated with 20 and 50 µM formaldehyde for 24 h, and the overproduced methylglyoxal in the conditioned medium collected from the tumor cells treated with formaldehyde triggered macrophage polarization towards M2 cells. Myricetin, a flavonol scavenging methylglyoxal, reversed the polarization of macrophages induced by methylglyoxal at 50 µM. These results not only provided essential evidences to reveal the molecular mechanisms of Warburg effect and metabolism-related immunosuppression related to formaldehyde exposure, but also indicated that methylglyoxal could be utilized as a target for therapeutic treatment or prevention of formaldehyde-induced immunotoxicity.

Epigallocatechin­3­gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer­associated fibroblasts.

In recent times, researchers working on tumor metabolism have paid increasing attention to the tumor microenvironment. Emerging evidence has confirmed that epigenetic modifications of cancer­associated fibroblasts (CAFs) alters the characteristics of glucose metabolism to achieve a symbiotic relationship with the cancer cells. Epigallocatechin­3­gallate (EGCG) exerts anti­tumor effects via a variety of mechanisms, although the underlying mechanism that accounts for the effects of EGCG on glucose metabolic alterations of CAFs have yet to be elucidated. In the present study, through co­culture with colorectal cancer (CRC) cells, human intestinal fibroblasts were transformed into CAFs, and exhibited enhanced aerobic glycolysis. Induced CAFs were able to enhance the proliferation, migration and invasion of CRC cells in vitro. EGCG treatment led to direct inhibition of the proliferation and migration of CRC cells; furthermore, EGCG treatment of CAFs suppressed their tumor­promoting capabilities by inhibiting their glycolytic activity. Blocking the lactic acid efflux of CAFs with a monocarboxylate transporter 4 (MCT4) inhibitor or through silencing MCT4 could also suppress their tumor­promoting capabilities, indicating that lactate fulfills an important role in the metabolic coupling that occurs between CAFs and cancer cells. Taken together, the results of the present study showed that EGCG targeting of the metabolism of tumor stromal cells provided a safe and effective strategy of anti­cancer therapy.

Glycolytic inhibition with 3-bromopyruvate suppresses tumor growth and improves survival in a murine model of anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer is a rare but devastating malignancy. Anaplastic thyroid cancer cells exhibit the Warburg effect by preferentially undergoing glycolysis even in aerobic conditions, leading to high glucose use. Here we assess if targeted inhibition of glycolysis can diminish anaplastic thyroid cancer growth and improve outcomes. METHODS: Human anaplastic thyroid cancer cell line 8505C was grown in medium containing high (25 mmol/L) or low (3 mmol/L) glucose concentration and hexokinase II inhibitor 3-bromopyruvate (200 µM). Cellular proliferation, migration, and invasion were measured. An orthotopic xenograft model of anaplastic thyroid cancer was generated in nude mice using 8505C cells. Animals were provided standard chow or a ketogenic diet and treated with 3-bromopyruvate (1.8 mg/kg). Overall survival time was monitored. Necropsies were performed to harvest tumors for analysis. RESULTS: Growth of 8505C in low-glucose medium with 3-bromopyruvate decreased cell proliferation by 89%, migration by 44%, and invasion by 73% (P < .001 for all) compared with high glucose. Animals concomitantly receiving a ketogenic diet and 3-bromopyruvate exhibited smaller tumor volumes (P = .03), slower tumor growth rates (P = .01), and improved overall survival (P = .006) compared with standard-diet control subjects. Monotherapy with a ketogenic diet or 3-bromopyruvate alone did not reduce tumor size or increase survival over the standard-diet control group. CONCLUSION: Glycolytic inhibition with 3-bromopyruvate inhibits tumor growth and extends survival in a murine model of anaplastic thyroid cancer when combined with the ketogenic diet. Thus, targeted glycolytic inhibition of anaplastic thyroid cancer exhibits context-specific utility and may only be effective during ketosis induced by dietary restriction of glycolytic inputs.

Therapeutic targeting of SPIB/SPI1-facilitated interplay of cancer cells and neutrophils inhibits aerobic glycolysis and cancer progression.

BACKGROUND: As a metabolic reprogramming feature, cancer cells derive most of their energy from aerobic glycolysis, while its regulatory mechanisms and therapeutic strategies continue to be illusive. METHODS: Integrative analysis of publically available expression profile datasets was used to identify critical transcriptional regulators and their target glycolytic enzymes. The functions and acting mechanisms of transcriptional regulators in cancer cells were investigated by using in vitro and in vivo assays. The Kaplan-Meier curve and log-rank assay were used to conduct the survival study. RESULTS: Salmonella pathogenicity island 1 (SPI1/PU.1), a haematopoietic transcription factor, was identified to facilitate glycolytic process, tumourigenesis, invasiveness, as well as metastasis of colon cancer cells, which was interplayed by tumour-associated neutrophils. Mechanistically, neutrophils delivered SPI1 mRNA via extracellular vesicles, resulting in enhanced SPI1 expression of cancer cells. Through physical interaction with SPI1-related protein (SPIB), SPI1 drove expression of glycolytic genes within cancer cells, which in turn induced polarization of neutrophils via glycolytic metabolite lactate. Depletion of neutrophils or SPIB-SPI1 interaction in cancer cells significantly inhibited glycolytic process, tumourigenesis and aggressiveness. Upregulation of SPI1 or SPIB was found to be associated with poor prognosis in patients suffering from colon cancer. CONCLUSIONS: Therapeutic targeting of SPIB/SPI1-facilitated interplay of cancerous cells and neutrophils suppresses aerobic glycolysis and progression of cancer.

Baicalein resensitizes tamoxifen-resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia-inducible factor-1α.

Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM-resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM-resistant cells. It also enhanced the TAM-induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan-Meier plotter database showed that HIF-1α expression was inversely correlated with TAM therapeutic response in NCI-60 cancer cells and breast cancer patients. HIF-1α expression was increased in TAM-resistant cells due to an increase in mRNA levels and reduced ubiquitin-mediated degradation. Baicalein reduced HIF-1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase-mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia-response element, and transcriptional activity of HIF-1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF-1α-targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF-1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM-induced mitochondrial apoptotic pathway. The HIF-1α stabilizer dimethyloxallyl glycine prevented the baicalein-induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM-induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF-1α-mediated aerobic glycolysis and mitochondrial dysfunction.

Zhoushi Qi Ling decoction represses docetaxel resistance and glycolysis of castration-resistant prostate cancer via regulation of SNHG10/miR-1271-5p/TRIM66 axis.

Docetaxel resistance developed in half of castration-resistant prostate cancer (CRPC) patients hinders its long-term clinical application. The current study was designed to investigate the effects of Chinese medicine Zhoushi Qi Ling decoction on the docetaxel resistance of prostate cancer as well as elucidate the underlying molecular mechanism. In our study, Qi Ling significantly decreased viability and colony formation as well as increased apoptosis of docetaxel-resistant (DR) CRPC cells. Qi Ling-treated DR cells exhibited decreased glucose consumption, lactate release and pyruvate production. Moreover, lncRNA SNHG10 was upregulated in DR tissues of CRPC patients and was negatively correlated with the progression-free survival. Bioinformatics analysis indicated miR-1271-5p as the associated miRNA possibly binding with SNHG10. miR-1271-5p up-regulation dramatically decreased the luciferase activity of SNHG10 in DR cells. SNHG10 knockdown sharply increased the expression of miR1271-5p in DR cells. Targetscan predicted TRIM66 as one of the downstream targets of miR-1271-5p. miR-1271-5p up-regulation drastically reduced luciferase activity as well as TRIM66 expression in DR cells. Also, the knockdown of SNHG10 remarkably suppressed the expression of TRIM66 in DR cells. Additionally, Qi Ling treatment reduced SNHG10 and TRIM66, while increased miR1271-5p, in DR cells. In summary, Qi Ling inhibited docetaxel resistance and glycolysis of CRPC possibly via SNHG10/miR-1271-5p/TRIM66 pathway.

Current Development and Application of Anaerobic Glycolytic Enzymes in Urothelial Cancer.

Urothelial cancer is a malignant tumor with metastatic ability and high mortality. Malignant tumors of the urinary system include upper tract urothelial cancer and bladder cancer. In addition to typical genetic alterations and epigenetic modifications, metabolism-related events also occur in urothelial cancer. This metabolic reprogramming includes aberrant expression levels of genes, metabolites, and associated networks and pathways. In this review, we summarize the dysfunctions of glycolytic enzymes in urothelial cancer and discuss the relevant phenotype and signal transduction. Moreover, we describe potential prognostic factors and risks to the survival of clinical cancer patients. More importantly, based on several available databases, we explore relationships between glycolytic enzymes and genetic changes or drug responses in urothelial cancer cells. Current advances in glycolysis-based inhibitors and their combinations are also discussed. Combining all of the evidence, we indicate their potential value for further research in basic science and clinical applications.

Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma.

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.

The Warburg effect as a therapeutic target for bladder cancers and intratumoral heterogeneity in associated molecular targets.

Bladder cancer is the 10th most common cancer worldwide. For muscle-invasive bladder cancer (MIBC), treatment includes radical cystectomy, radiotherapy, and chemotherapy; however, the outcome is generally poor. For non-muscle-invasive bladder cancer (NMIBC), tumor recurrence is common. There is an urgent need for more effective and less harmful therapeutic approaches. Here, bladder cancer cell metabolic reprogramming to rely on aerobic glycolysis (the Warburg effect) and expression of associated molecular therapeutic targets by bladder cancer cells of different stages and grades, and in freshly resected clinical tissue, is investigated. Importantly, analyses indicate that the Warburg effect is a feature of both NMIBCs and MIBCs. In two in vitro inducible epithelial-mesenchymal transition (EMT) bladder cancer models, EMT stimulation correlated with increased lactate production, the end product of aerobic glycolysis. Protein levels of lactate dehydrogenase A (LDH-A), which promotes pyruvate enzymatic reduction to lactate, were higher in most bladder cancer cell lines (compared with LDH-B, which catalyzes the reverse reaction), but the levels did not closely correlate with aerobic glycolysis rates. Although LDH-A is expressed in normal urothelial cells, LDH-A knockdown by RNAi selectively induced urothelial cancer cell apoptotic death, whereas normal cells were unaffected-identifying LDH-A as a cancer-selective therapeutic target for bladder cancers. LDH-A and other potential therapeutic targets (MCT4 and GLUT1) were expressed in patient clinical specimens; however, positive staining varied in different areas of sections and with distance from a blood vessel. This intratumoral heterogeneity has important therapeutic implications and indicates the possibility of tumor cell metabolic coupling.

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer.

Lung cancer is one of the most lethal diseases and therefore poses a significant threat to human health. The Warburg effect, which is the observation that cancer cells predominately produce energy through glycolysis, even under aerobic conditions, is a hallmark of cancer. 6­phosphofructo­2­kinase/fructose­2,6­biphosphatase 2 (PFKFB) is an important regulator of glycolysis. Shikonin is a Traditional Chinese herbal medicine, which has been reported to exert antitumor effects. The present study aimed to investigate the anticancer activity of shikonin in lung cancer. Cell Counting Kit­8 (CCK­8) and colony formation assays were used to analyze proliferation in A549 and H446 cells. Wound healing and Transwell assays were used to measure migration and invasion in A549 and H446 cells. Cell apoptosis was analyzed using flow cytometry. Lactate levels, glucose uptake and cellular ATP levels were measured using their corresponding commercial kits. Western blotting was performed to analyze the protein expression levels of key enzymes involved in aerobic glucose metabolism. Reverse transcription­quantitative PCR was used to analyze the mRNA expression levels of PFKFB2. The results of the present study revealed that PFKFB2 expression levels were significantly upregulated in NSCLC tissues. Shikonin treatment decreased the proliferation, migration, invasion, glucose uptake, lactate levels, ATP levels and PFKFB2 expression levels and increased apoptosis in lung cancer cells in a dose­dependent manner. The overexpression of PFKFB2 increased the proliferation, migration, glucose uptake, lactate levels and ATP levels in lung cancer cells, while the knockdown of PFKFB2 expression exerted the opposite effects. Moreover, there were no significant differences in lung cancer cell migration, apoptosis, glucose uptake, lactate levels and ATP levels between cells with knocked down PFKFB2 expression or treated with shikonin and the knockdown of PFKFB2 in cells treated with shikonin. In conclusion, the results of the present study revealed that shikonin inhibited the Warburg effect and exerted antitumor activity in lung cancer cells, which was associated with the downregulation of PFKFB2 expression.

Part-time cancers and role of melatonin in determining their metabolic phenotype.

This brief review describes the association of the endogenous pineal melatonin rhythm with the metabolic flux of solid tumors, particularly breast cancer. It also summarizes new information on the potential mechanisms by which endogenously-produced or exogenously-administered melatonin impacts the metabolic phenotype of cancer cells. The evidence indicates that solid tumors may redirect their metabolic phenotype from the pathological Warburg-type metabolism during the day to the healthier mitochondrial oxidative phosphorylation on a nightly basis. Thus, they function as cancer cells only during the day and as healthier cells at night, that is, they are only part-time cancerous. This switch to oxidative phosphorylation at night causes cancer cells to exhibit a reduced tumor phenotype and less likely to rapidly proliferate or to become invasive or metastatic. Also discussed is the likelihood that some solid tumors are especially aggressive during the day and much less so at night due to the nocturnal rise in melatonin which determines their metabolic state. We further propose that when melatonin is used/tested in clinical trials, a specific treatment paradigm be used that is consistent with the temporal metabolic changes in tumor metabolism. Finally, it seems likely that the concurrent use of melatonin in combination with conventional chemotherapies also would improve cancer treatment outcomes.

Recent advancements in therapeutic targeting of the Warburg effect in refractory ovarian cancer: A promise towards disease remission.

Epithelial ovarian cancer, the most lethal gynecological malignancy, is diagnosed at advanced stage, recurs and displays chemoresistance to standard chemotherapeutic regimen of taxane/platinum drugs. Despite development of recent therapeutic approaches including poly-ADP ribose polymerase inhibitors, this fatal disease is diagnosed at advanced stage and heralds strategies for early detection and improved treatment. Recent literature suggests that high propensity of ovarian cancer cells to consume and metabolize glucose via glycolysis even in the presence of oxygen (the 'Warburg effect') can significantly contribute to disease progression and chemoresistance and hence, it has been exploited as novel drug target. This review focuses on the molecular cues of aberrant glycolysis as drivers of chemo-resistance and aggressiveness of recurrent ovarian cancer. Furthermore, we discuss the status quo of small molecule inhibition of aerobic glycolysis and significance of metabolic coupling between cancer cells and tumor microenvironment as novel therapeutic interventions against this lethal pathology.

Targeting pyruvate dehydrogenase kinase signaling in the development of effective cancer therapy.

Pyruvate is irreversibly decarboxylated to acetyl coenzyme A by mitochondrial pyruvate dehydrogenase complex (PDC). Decarboxylation of pyruvate is considered a crucial step in cell metabolism and energetics. The cancer cells prefer aerobic glycolysis rather than mitochondrial oxidation of pyruvate. This attribute of cancer cells allows them to sustain under indefinite proliferation and growth. Pyruvate dehydrogenase kinases (PDKs) play critical roles in many diseases because they regulate PDC activity. Recent findings suggest an altered metabolism of cancer cells is associated with impaired mitochondrial function due to PDC inhibition. PDKs inhibit the PDC activity via phosphorylation of the E1a subunit and subsequently cause a glycolytic shift. Thus, inhibition of PDK is an attractive strategy in anticancer therapy. This review highlights that PDC/PDK axis could be implicated in cancer's therapeutic management by developing potential small-molecule PDK inhibitors. In recent years, a dramatic increase in the targeting of the PDC/PDK axis for cancer treatment gained an attention from the scientific community. We further discuss breakthrough findings in the PDC-PDK axis. In addition, structural features, functional significance, mechanism of activation, involvement in various human pathologies, and expression of different forms of PDKs (PDK1-4) in different types of cancers are discussed in detail. We further emphasized the gene expression profiling of PDKs in cancer patients to prognosis and therapeutic manifestations. Additionally, inhibition of the PDK/PDC axis by small molecule inhibitors and natural compounds at different clinical evaluation stages has also been discussed comprehensively.

Therapeutic Approach of KRAS Mutant Tumours by the Combination of Pharmacologic Ascorbate and Chloroquine.

The Warburg effect has been considered a potential therapeutic target to fight against cancer progression. In KRAS mutant cells, PKM2 (pyruvate kinase isozyme M2) is hyper-activated, and it induces GLUT1 expression; therefore, KRAS has been closely involved in the initiation of Warburg metabolism. Although mTOR (mammalian target of rapamycin), a well-known inhibitor of autophagy-dependent survival in physiological conditions, is also activated in KRAS mutants, many recent studies have revealed that autophagy becomes hyper-active in KRAS mutant cancer cells. In the present study, a mathematical model was built containing the main elements of the regulatory network in KRAS mutant cancer cells to explore the further possible therapeutic strategies. Our dynamical analysis suggests that the downregulation of KRAS, mTOR and autophagy are crucial in anti-cancer therapy. PKM2 has been assumed to be the key switch in the stress response mechanism. We predicted that the addition of both pharmacologic ascorbate and chloroquine is able to block both KRAS and mTOR pathways: in this case, no GLUT1 expression is observed, meanwhile autophagy, essential for KRAS mutant cancer cells, is blocked. Corresponding to our system biological analysis, this combined pharmacologic ascorbate and chloroquine treatment in KRAS mutant cancers might be a therapeutic approach in anti-cancer therapies.